PROJECT SUMMARY/ ABSTRACT Electronic cigarettes (e-cigarettes) are novel battery powered nicotine delivery devices. Although the prevalence of e-cigarette use is increasing, there remains a lack of research regarding their safety and addiction potential. A growing body of research suggests that like tobacco cigarettes, e-cigarettes also share a high rate of co-use with alcohol. Previous research has found that smoking tobacco cigarettes while drinking alcohol may produce greater rewarding effects. However, there are over 5,000 different compounds found in tobacco smoke in addition to nicotine, some of which are also psychoactive. A challenge to dissociating the effects of nicotine from tobacco has been administering nicotine in a way that is comparable to smoking a cigarette, since the route of administration influences the subjective effects of nicotine. E-cigarettes can deliver amounts of nicotine similar to tobacco cigarettes and allow for a matched placebo control (same flavor, device, and sensory experience) between the nicotine and the nicotine-free e-cigarette condition. The proposed research will take advantage of this novel route of administration to examine the hypothesis that alcohol and nicotine delivered through an e-cigarette have combined pharmacological effects that could support their co- use. This hypothesis will be addressed with the following two Specific Aims: (1) To determine if nicotine e- cigarettes have greater subjective rewarding effects when used in combination with alcohol, and (2) To determine if ad libitum nicotine e-cigarette use increases after drinking alcohol. The proposed research will use a three-day within-subject human laboratory study. On each test day participants will drink an alcohol or placebo-alcohol beverage. Participants will then use their own e-cigarette (with or without nicotine) in a standardized e-cigarette puffing protocol, followed by a 2-hour ad libitum e-cigarette use session. Each participant will complete three experimental conditions on three separate days: (1) nicotine e-cigarette + alcohol, (2) nicotine e-cigarette + placebo alcohol, and (3) nicotine-free e-cigarette + alcohol. Data from the standardized e-cigarette session will be used to assess the subjective and cardiovascular effects of e- cigarettes when used alone or in combination with alcohol. The ad libitum session will provide information on the use behavior and plasma nicotine levels reached when e-cigarettes are used alone versus after drinking alcohol. This work will provide important training in human pharmacology research as I transition from work in mice to humans. This research and training will create a solid foundation for me to become an independent investigator. Knowledge produced by the proposed study will have important implications for informing future regulatory actions regarding e-cigarettes and other alternative nicotine delivery devices and improve our understanding of the role of nicotine in the co-morbid use of alcohol and tobacco.